1. Field of the Invention
The present invention relates to a method for monitoring hepatic disease or dysfunction. More specifically, the invention relates to administering labeled methionine or methionine metabolites to an individual and assessing expired labeled carbon dioxide.
2. Description of the Prior Art
Standard serologic and biochemical serum liver tests have been used to determine the presence of liver disease. However, these tests do not provide an accurate assessment of hepatic functional capacity nor do they detect changes in hepatic disease severity (Gitnick, G. Surg. Clin. N. Am. 61:197-207 1981!). Increasing prothrombin time and decreasing serum albumin concentrations have been used as prognostic indicators of progressive liver disease (Rydning, A., et al. Scand. J. Gastroenterol. 25:119-126 1990!). Significant changes in prothrombin time and albumin may occur in patients for reasons other than liver dysfunction and, at times, only after severe liver decompensation. Further, radiological testing and histological examination of liver biopsies are poor indicators of decreasing hepatic function.
The Child-Pugh (CP) classification is used to determine the degree of liver disease severity. The CP classification reflects the sum of scores derived from clinical and laboratory parameters. Disadvantages of the CP classification include subjective measures (degree of ascites and encephalopathy) and dependence on serum tests (bilirubin, albumin, and prothrombin time) that may be influenced by extrahepatic factors. As a result, the CP classification is a poor measure of patient status and is insensitive to small changes in the patient's condition.
During the last twenty years, much work has been devoted to devising quantitative liver tests. Liver function can be subdivided into three compartments: 1) cytosolic, 2) microsomal, and 3) mitochondrial. Each compartment's function can be evaluated with both quantitative serum and breath tests.
Blood and breath tests have been used for assessing mitochondrial-compartment hepatic function. A typical blood test is the measurement of the arterial ketone body ratio (AKBR). The hepatic mitochondrial redux potential ratio (ratio of NAD/NADH) correlates with the ketone body ratio (acetoacetate/.beta.-hydroxy butyrate) in liver disease. Serial changes in the AKBR can predict hepatic dysfunction, postoperative graft viability, and acute rejection (Asonuma K., S., et al. Transplantation. 51:164-171 1991!, Mori K, K., et al. Ann. Surg. 211:438-446 1990!) post liver transplantation. However, recent experiments by Matsushita et al. determined that extrahepatic metabolism of ketone bodies diminishes the value of the AKBR (Matsushita K. et al. Hepatology. 20:331-335 1994!). Additional disadvantages of the AKBR are its labor-intensiveness and the requirement for arterial blood.
Breath tests can also be used to access the mitochondrial compartment hepatic function. The first substrate used as a breath test to measure mitochondrial function was the keto-analog of leucine ketoisocaproic acid (KICA) (Michaletz P. A., et al. Hepatology. 10:829-832 1989!). Decarboxylation of KICA occurs mainly in hepatic mitochondria since anhepatic animals have a 75% reduction in .sup.14 CO.sub.2 production. Alcohol, which is known to alter the NAD/NADH ratio, deceases KICA decarboxylation. Further experiments with sodium salicylate, an uncoupler of mitochondrial respiration, showed an increase in KICA decarboxylation.
The .sup.13 C and .sup.14 C-KICA breath tests have been used to access mitochondrial function in controls and in patients with alcoholic and non-alcoholic liver disease (Lauterburg B H, et al. Hepatology 17:418-422 1993!). The KICA breath test showed impaired mitochondrial function in the alcoholic patients compared to controls and non-alcoholic patients. Patients with alcoholic disease had normal aminopyrine breath test and galactose elimination capacity (both measurements of cytosolic function) despite decreased mitochondrial function. These results suggest that KICA decarboxylation reflects hepatic mitochondrial function in patients with chronic alcoholic liver disease.
The .sup.13 C-KICA breath test has also been used to differentiate between alcoholic and nonalcoholic liver-diseased patients (Witschi, A., et al. Alcohol Clin. Exp. Res. 18:951-955 1994!, Mion F, et al. Metabolism. 44:699-700 1995!). Lauterburg and co-workers have shown that the .sup.13 C-KICA test can detect mitochondrial changes with the ingestion of the equivalent of two alcoholic drinks or with therapeutic doses of acetylsalicylic acid (ASA, aspirin) (Lauterburg B H, et al. J. Lab. Clin. Med. 125:378-383 1995!). However, the KICA breath test is not widely used. Disadvantages of the KICA breath test are the high cost of the stable isotope and its instability in solution.
These and other disadvantages of the prior art are overcome by the present invention. As shown herein, we provide a novel breath test for assessing hepatic disease or dysfunction.